Aminomethyloxooxazlidinyl arylbenzene derivatives useful as antibacterial agents

ABSTRACT

Novel aminomethyloxooxazolidinyl arylbenzene derivatives, wherein the aryl includes the phenyl, substituted phenyl, pyridyl, and substituted pyridyl groups, such as (l)-N-{3-[4-(4 &#39;-pyridyl)phenyl]-2-oxooxazolidin-5-ylmethyl}acetamide, possess useful antibacterial activity.

This is a division of application Ser. No. 07/225,809 filed Jul. 29,1988, now U.S. Pat. No. 4,948,801

TECHNICAL FIELD

This invention relates to aminomethyloxooxazolidinyl arylbenzenederivatives, their preparation, to pharamaceutical compositionscontaining them, and to methods of using them to alleviate bacterialinfections.

BACKGROUND OF THE INVENTION

At the present time, no existing antibacterial product provides allfeatures deemed advantageous for such a product. There is continualdevelopment of resistance by bacterial strains. A reduction of allergicreactions and of irritation at the site of injection, and greaterbiological half-life (i.e., longer in vivo activity) are currentlydesirable features for antibacterial products.

U.S. Pat. No. 4,128,654 issued to Fugitt et al. on Dec. 5, 1978,discloses, among others, compounds of the formula: ##STR1## whereA=RS(O)_(n) ;

X=Cl, Br or F;

R=C₁ -C₃ alkyl; and

n=0, 1 or 2.

The compounds are disclosed as being useful in controlling fungal andbacterial diseases of plants.

U.S. Pat. No. Re. 29,607 reissued Apr. 11, 1978 discloses derivatives of5-hydroxymethyl-3-substituted-2-oxazolidinones of the formula: ##STR2##where R is H, F, CH₃, or CF₃. Such compounds are described as havingantidepressive, tranquilizing, sedative, and antiinflammatoryproperties.

U.S. Pat. No. 4,250,318, which was issued on Feb. 10, 1981, disclosesantidepressant compounds of the formula: ##STR3## where R' can be, amongothers, a para-n-pentylamino group, an SR₁ group where R₁ is C₁ -C₅alkyl, or an acetylmethylthio group.

U.S. Pat. No. 4,340,606, issued to Fugitt et al. on Jul. 20, 1982,discloses antibacterial agents of the general formula: ##STR4## where R₁=CH₃, C₂ H₅, CF₂ H, CF₃ or CF₂ CF₂ H; and

X=OR₂ (R₂ =H or various acyl moieties).

U.S. Pat. No. 3,687,965, issued to Fauran et al. on Aug. 29, 1972,discloses compounds of the formula: ##STR5## where --N(R₁) (R₂)represents either dialkylamino radical in which the alkyl portions haveone to five carbon atoms, or a heterocyclic amino radical which may besubstituted by an alkyl radical having one to five carbon atoms or by apyrrolidinocarbonylmethyl radical, and

R₃ represents a phenyl radical which may be substituted by one or moreof the following radicals:

an alkoxy radical having one to five carbon atoms;

a halogen atom;

a trifluoromethyl radical, or

a carboxyl radical which may be esterified.

The patent states that these compounds possess hypotensive,vasodilatatory, spasmolytic, sedative, myorelaxant, analgesic andantiinflammatory properties. There is no mention of antibacterialproperties.

Belgian Patent 892,270, published Aug. 25, 1982, discloses monoamineoxidase inhibitors of the formula ##STR6## where R is H, C₁ -C₄ alkyl orpropargyl;

Ar is phenyl, optionally substituted by halo or trifluoromethyl;

n is 0 or 1; and

X is --CH₂ CH₂ --, --CH═CH--, an acetylene group or --CH₂ O--.

U.S. Pat. No. 4,461,773 issued to W. A. Gregory on Jul. 24, 1984discloses antibacterial agents of the formula ##STR7## wherein, for thel, and mixtures of the d and l stereoisomers of the compound,

R₁ is R₂ SO₂, ##STR8## R₂ is --NR₃ R₄, --N(OR₃)R₄, --N₃, --NHNH₂, --NX₂,--NR₆ X, --NXZ, ##STR9## or --N═S(O)_(n) R₈ R₉ ; R₃ and R₄ areindependently H, alkyl of 1-4 carbons or cycloalkyl of 3-8 carbons;

R₅ is NR₃ R₄ or OR₃ ;

R₆ is alkyl of 1-4 carbons;

R₇ is alkyl of 1-4 carbons, optionally substituted with one or morehalogens;

R₈ and R₉ are independently alkyl of 1-4 carbons or, taken together are--(CH₂)_(p) --;

R₁₀ is H, alkyl of 1-3 carbons, ##STR10## R₁₁ is alkyl of 1-12 carbons;R₁₂ is H, alkyl of 1-5 carbons, CH₂ OH or CH₂ SH;

X is Cl, Br or I;

Z is a physiologically acceptable cation;

m is 2 or 3;

n is 0 or 1; and

p is 3, 4 or 5;

and when R₁₀ is alkyl of 1-3 carbons, R₁ can also be CH₃ S(O)_(q) whereq is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

U.S. Pat. No. 4,705,799 issued to Gregory on Nov. 10, 1987 disclosesantibacterial agents of the formula: ##STR11## wherein, for the l, andmixtures of the d and l stereoisomers of the compound,

A is --NO₂, --S(O)_(n) R₁, --S(O)₂ --N═S(O)_(p) R₂ R₃, --SH, ##STR12##alkyl of 1 to 8 carbons, optionally substituted with one or more halogenatoms, OH, ═0 other than at alpha position, S(O)_(n) R₂₄, NR₅ R₆,alkenyl of 2-5 carbons, alkynyl of 2-5 carbons or cycloalkyl of 3-8carbons;

R₁ is C₁ -C₄ alkyl, optionally substituted with one or more halogenatoms, OH, CN, NR₅ R₆ or CO₂ R₈ ; C₂ -C₄ alkenyl; --NR₉ R₁₀ ; --N₃ ;##STR13## --NX₂ ; NR₉ X --⁻ NXZ⁺ ; R₂ and R₃ are independently C₁ -C₂alkyl or, taken together are --(CH₂)_(q) --;

R₄ is alkyl of 1-4 carbons, optionally substituted with one or morehalogens;

R₅ and R₆ are independently H, alkyl of 1-4 carbons or cycloalkyl of 3-8carbons;

R₇ is --NR₅ R₆, --OR₅ or ##STR14## R₈ is H or alkyl of 1-4 carbons; R₉is H, C₁ -C₄ alkyl or C₃ -C₈ cycloalkyl;

R₁₀ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₄ cycloalkyl, --OR₈ or--NR₁₁ R_(11A) ;

R₁₁ and R_(11A) are independently H or C₁ -C₄ alkyl, or taken together,are --(CH₂)_(r) --;

X is Cl, Br or I;

Y is H, F, Cl, Br, alkyl of 1-3 carbons, or NO₂, or A and Y takentogether can be --O-- (CH₂)_(t) O--;

Z is a physiologically acceptable cation;

n is 0, 1 or 2;

p is 0 or 1;

q is 3, 4 or 5;

r is 4 or 5;

t is 1, 2 or 3;

B is --NH₂, ##STR15## or N₃ ; R₁₂ is H, C₁ -C₁₀ alkyl or C₃ -C₈cycloalkyl;

R₁₃ is H; C₁ -C₄ alkyl optionally substituted with one or more halogenatoms; C₂ -C₄ alkenyl; C₃ -C₄ cycloalkyl; phenyl; --CH² OR₁₅ ;--CH(OR₁₆)OR₁₇ ; --CH₂ S(O)_(v) R₁₄ ; ##STR16## --OR₁₈ ; --SR₁₄ ; --CH₂N₃ ; the aminoalkyl groups derived from α-amino acids such as glycine,L-alanine, L-cysteine, L-proline, and D-alanine; --NR₁₉ R₂₀ ; orC(NH₂)R₂₁ R₂₂ ;

R₁₄ is C₁ -C₄ alkyl, optionally substituted with one or more halogenatoms;

R₁₅ is H or C₁ -C₄ alkyl, optionally substituted with one or morehalogen atoms;

R₁₆ and R₁₇ are independently C₁ -C₄ alkyl or, taken together, are--(CH₂)_(m) --;

R₁₈ is C₁ -C₄ alkyl or C₇ -C₁₁ aralkyl;

R₁₉ and R₂₀ are independently H or C₁ -C₂ alkyl;

R₂₁ and R₂₂ are independently H, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, phenylor, taken together, are --(CH₂)_(s) --;

u is 1 or 2;

v is 0, 1 or 2;

m is 2 or 3;

s is 2, 3, 4 or 5; and

R₂₃ is H, alkyl of 1-8 carbons optionally substituted with one or morehalogens, or cycloalkyl of 3-8 carbons;

R₂₄ is alkyl of 1-4 carbons or cycloalkyl of 3-8 carbons;

R₂₅ is alkyl of 1-4 carbons substituted with one or more of --S(O)_(n)R₂₄, --OR₈, ##STR17## --NR₅ R₆, or alkenyl of 2-5 carbons optionallysubstituted with CHO;

or a pharmaceutically suitable salt thereof; provided that:

1) when A is CH₃ S--, then B is not ##STR18## 2) when A is CH₃ SO₂ --,then B is not ##STR19## 3) when A is H₂ NSO₂ -- and B is ##STR20## thenR₁₂ is H; 4) when A is --CN, B is not --N₃ ;

5) when A is (CH₃)₂ CH, B is not NHCOCH₂ Cl;

6) when A is OR₅, then B is not NH₂ ;

7) when A is F, then B is not NHCO₂ CH₃.

None of the above-mentioned references suggest the novel antibacterialcompounds of this invention.

SUMMARY OF THE INVENTION

According to the present invention, there is provided an arylbenzeneoxazolidinone of the formula: ##STR21## wherein, for the l, and mixturesof the d and l stereoisomers of the compound

Ar is an aromatic group selected from the group consisting of ##STR22##diazinyl group optionally substituted with X and Y, a triazinyl groupoptionally substituted with X and Y, ##STR23## Z is O, S, or NR₅ ; W isCH or N, or also can be S or O when Z is NR₅ ;

X independently is H, --NO₂, --S(O)_(n) R₁, tetrazoyl, --S(O)₂--N═S(O)_(p) R₂ R₃, --SH, ##STR24## alkyl of 1 to 8 carbons optionallysubstituted with one or more halogen atoms, OH, ═O other than at alphaposition, S(O)_(n) R₂₄, or NR₅ R₆, alkenyl of 2-5 carbons or cycloalkylof 3-8 carbons;

R₁ is C₁ -C₄ alkyl, optionally substituted with one or more halogenatoms, OH, CN, NR₅ R₆ or CO₂ R₈ ; C₂ -C₄ alkenyl; --NR₉ R₁₀ ; --N₃ ;##STR25## --NG₂ ; NR₉ G--⁻ NGM⁺ ; R₂ and R₃ are independently C₁ -C₂alkyl or, taken together are --(CH₂)_(q) --;

R₄ is alkyl of 1-4 carbons, optionally substituted with one or morehalogens;

R₅ and R₆ are independently H, alkyl of 1-8 carbons, cycloalkyl of 3-8carbons --(CH₂)_(t) OR₈, --(CH₂)_(t) NR₁₁ R_(11a), or --O(CH₂)_(t) NR₁₁R_(11a) ; or taken together are --(CH₂)₂ O(CH₂)₂ --, --(CH₂)_(t)CH(COR₄)--, or ##STR26## R₇ is --NR₅ R₆, --OR₅ or ##STR27## R₈ is H oralkyl of 1-4 carbons; R₉ is H, C₁ -C₄ alkyl or C₃ -C₈ cycloalkyl;

R₁₀ is H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₄ cycloalkyl, --OR₈ or--NR₁₁ R_(11A) ;

R₁₁ and R_(11A) are independently H or C₁ -C₄ alkyl, or taken together,are --(CH₂)_(r) --;

G is Cl, Br or I;

Y independently is H, F, Cl, Br, OR₈, alkyl of 1-3 carbons, or NO₂ ;

X and Y taken together (a) when Ar is ##STR28## to form a fusedsix-membered carbocyclic ring, or (b) when Ar is ##STR29## to form##STR30## M is a physiologically acceptable cation; n is 0, 1 or 2

p is 0 or 1;

q is 3, 4 or 5;

r is 4 or 5;

t is 1, 2 or 3;

Q is --NH₂, ##STR31## or N₃ ; R₁₂ is H, C₁ -C₁₀ alkyl or C₃ -C₈cycloalkyl;

R₁₃ is H; C₁ -C₄ alkyl optionally substituted with one or more halogenatoms; C₂ -C₄ alkenyl; C₃ -C₄ cycloalkyl; phenyl; --CH₂ OR₁₅ ;--CH(OR₁₆)OR₁₇ ; --CH₂ S(O)_(v) R₁₄ ; ##STR32## --OR₁₈ ; SR₁₄ ; --CH₂ N₃; the aminoalkyl groups derived from α-amino acids such as glycine,L-alanine, L-cysteine, L-proline, and D-alanine; --NR₁₉ R₂₀ ; or--C(NH₂)R₂₁ R₂₂ ;

R₁₄ is C₁ -C₄ alkyl, optionally substituted with one or more halogenatoms;

R₁₅ is H or C₁ -C₄ alkyl, optionally substituted with one or morehalogen atoms;

R₁₆ and R₁₇ are independently C₁ -C₄ alkyl or, taken together, are--(CH₂)_(m) --;

R₁₈ is C₁ -C₄ alkyl or C₇ -C₁₁ aralkyl;

R₁₉ and R₂₀ are independently H or C₁ -C₂ alkyl;

R₂₁ and R₂₂ are independently H, C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl, phenylor, taken together, are --(CH₂)_(s) --;

u is 1 or 2;

v is 0, 1 or 2;

m is 2 or 3;

s is 2, 3, 4 or 5;

R₂₃ is H, alkyl of 1-8 carbons optionally substituted with one or morehalogens, cycloalkyl of 3-8 carbons, alkyl of 1-4 carbons substitutedwith one or more of --S(O)_(n) R₂₄, --OR₈, ##STR33## or --NR₅ R₆ ; oralkenyl of 2-5 carbons optionally substituted with CHO or CO₂ R₈ ;

R₂₄ is alkyl of 1-4 carbons or cycloalkyl of 3-8 carbons; and

R₂₅ is R₆ or NR₅ R₆ ;

or a pharmaceutically suitable salt thereof; provided that:

1) when Q is NH₂, then Ar is not phenyl optionally substituted withhalogen or CF₃.

When used herein, the term "a diazinyl group optionally substituted withX and Y" means the following groups: ##STR34##

When used herein, the term "a triazinyl group optionally substitutedwith X and Y" means the following groups: ##STR35##

Also provided is a pharmaceutical composition consisting essentially ofa suitable pharmaceutical carrier and a compound of Formula (I) and amethod of using a compound of Formula (I) to treat bacterial infectionin a mammal.

Further provided is a process for preparing compounds of Formula (I),such a process being described in detail hereinafter.

PREFERRED EMBODIMENTS

1. Preferred Ar groups are: ##STR36## where X and Y are as defined.

More preferred Ar groups are those preferred Ar groups where Y is H.

Most preferred Ar groups are the preferred Ar groups where Y is H and Xis H, alkyl of 1-5 carbon atoms, --SCH₃, --SOCH₃, --SO₂ CH₃, ##STR37##OR₅, --CH₂ NR₅ R₆, R₆ R₅ N(CH₂)₂ CH(OH)--, or --CN.

2. A preferred Q group is: ##STR38## where R₁₃ is H, CH₃, --OR₁₈, CH₂Cl, CH₂ OH, or CH₂ OCH₃.

Preferred Q groups are ##STR39## and ##STR40## is specificallypreferred.

Specifically preferred compounds are:

(l)-N-[3-(4-phenylphenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(4-(4'-acetylphenyl)phenyl)-2-oxooazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(4-(4'-methylsulfinylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(4-(4'-methylsulfonylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(4-(4'-cyanophenyl)phenyl-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(4-(4'-diethylaminomethylphenyl)-phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(4-(4'-di-n-propylaminomethylphenyl)-phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(4-(4'-(3-N,N-dimethylamino-1-hydroxypropyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(4-(4'-(1-hydroxy-3-(4-morpholinyl)-propyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide;

(l)-N-[3-(4-(4'-pyridylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide,hydrochloride;

(l)-N-[3-(4-(3'-pyridylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide,hydrochloride.

DETAILED DESCRIPTION

The compounds of Formula (I) contain at least one chiral center, and assuch exist as two individual isomers or as a mixture of both. Thisinvention relates to the levorotatory isomer (l) which for many of thecompounds in this invention can be referred to as the (S) isomer, aswell as mixtures containing both the (d) or (R) and (S) isomers.Additional chiral centers may be present in the groups Ar and/or B; andthis invention relates to all possible stereoisomers in these groups.

For the purpose of this invention, the l-isomer of compounds of Formula(I) is intended to mean compounds of the configuration depicted; when Bis NHAc, and closely related groups, this isomer is described as the(S)-isomer in the Cahn-Ingold-Prelog nomenclature: ##STR41##

SYNTHESIS

Compounds of Formula (I) can be prepared as follows: ##STR42##

In Scheme 1, R₂₃ is H or alkyl of 1-8 carbons optionally substitutedwith a halogen or a terminal carboxylic acid or its salts. R₅, R₆, and Bare as described previously. R₈ is H or alkyl of 1-4 carbons optionallysubstituted with a terminal carboxylic acid or its salts.

The compound (II) is converted to a compound of Formula (III) accordingto the process exactly paralleling that which was previously describedin U.S. Pat. No. 4,705,799. The Q groups in the Formula (I) can beselected from a variety of groups described and prepared according tothe procedures disclosed in the above patent.

A compound of Formula (III) is acylated with acetic anhydride, propionicanhydride, chloroacetic anhydride or succinic anhydride also accordingto the process described in the aforesaid patent to give a compound ofFormula (IV). Reaction of a compound of Formula (IV) with a substitutedhydrazine in a solvent such as ethanol, methanol or THF at 20° C. tounder refluxing temperature of the solvent chosen gives a hydrazone ofFormula (V), which can be reduced to a hydrazine derivative of Formula(VI) by reduction using a borohydride such as sodium cyanoborohydride inmethanol at 25° to 55° C.

A compound of Formula (III) is iodinated with iodine monochloride in anacetic acidtrifluoroacetic acid mixture at 40° to 70° C. to a compoundof Formula (VII), which can be converted to a cyano compound of Formula(VIII) by reaction with cuprous cyanide. The cyano group of a compoundof (VIII) can be converted to a tetrazole derivative of Formula (IX) byreaction with trimethylsilyl azide in DMF at 120°-145° C. Aniodocompound (VII) can also be converted to an aldehyde of Formula (X)by addition of carbon monoxide in a suitable solvent such as THF, glymeand DMF or mixtures thereof at 40° to 70° C. in the presence of acatalyst such as tributyltin hydride andtetrakis(triphenylphosphine)palladium(0). An aldehyde of (X) can beconverted to the corresponding carboxylic acid of Formula (XI) byoxidation with variety of oxidants such as chromic acid. An aldehyde of(X) can also be reductively aminated with an alkylamine such asdiethylamine, ethylmethylamine or methylpiperidine in an alcoholicsolvent using a reducing agent such as sodium cyanoborohydride and zincchloride at 0° to 35° C. to give an amine of Formula (XII).

Mannich reaction of a ketone of Formula (IV) with variety of alkylaminespreviously described gives a Mannich base of Formula (XIII) which can bereduced to an alcohol of Formula (XIV) with a borohydride reducing agentsuch as sodium cyanoborohydride in methanol. An alcohol of Formula (XIV)can be converted to a half ester of a dibasic acid of Formula (XV) bytreatment with a dibasic acid anhydride such as succinic or glutaricanhydrides. When the Mannich reaction is carried out with a ketone ofFormula (IV), where R₂₃ is ethyl, with dimethylamine, an unsaturatedketone of Formula (XVI) is also obtained.

A ketone of Formula (IV), when reacted with an hydroxylamine or acarboxymethyloxyamine in ethanol in the presence of pyridine, producesthe corresponding oxime of Formula (XVII). An oxime of Formula (XVII)can be converted to the oximino half ester of a dibasic carboxylic acidof Formula (XVIII) by reaction with a dibasic acid anhydride such assuccinic and glutaric anhydrides.

A ketone or aldehyde of Formulae (IV) and (X) can be reduced to acorresponding alcohol of Formula (XIX) by a reducing agent such assodium borohydride. An alcohol of Formula (XIX) can be esterified with amono- or dibasic acid anhydride to give a corresponding ester of Formula(XX). ##STR43##

As shown in Scheme 2, Ar is as described previously provided that itcontains no active hydrogen, (i.e., no NH, OH or SH), M is a zincchloride, trialkyltin or boronic acid radical and the catalyst can beselected from one of the many palladium or nickel coordination compoundssuch as bis(triphenylphosphine)palladium(II) chloride,tri(2-tolyl)phosphine and palladium(II) acetate, orbis(triphenylphosphine)nickel(II) chloride. An aromatic bromide ofFormula (XXI) is converted to a corresponding Grignard reagent withmagnesium or to a lithium reagent with alkyllithium by the usualprocedures which are well known in the art. A reagent of Formula (XXII)is converted to an organozinc chloride compound with zinc chloride, to atrialkyltin compound with trialkyltin chloride or to a boronic acid withtriisopropylborate, each followed by basic hydrolysis in a suitablesolvent such as ether, THF or glyme. Alternatively, when Ar containsactive hydrogens, an organotin compound of Formula (XXIII) can beprepared by a palladium catalyzed reaction with a bistrialkyltinreagent. A resulting organometallic compound of Formula (XXIII) is crosscoupled with a 3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl derivative ofFormula (XXIV) in a suitable solvent such as THF or DMF in the presenceof a catalyst usually selected from those previously described. Thecross coupling reaction works equally well when an aryliodide and a3-(4-trialkylstannylphenyl)-2-oxooxazolidinyl derivative is reacted inthe same manner. The iodo compound of Formula (XXIV) is prepared byiodinating (l)-N-(3-phenyl-2-oxooxazolidin-5-ylmethyl)acetamide usingiodine and silver trifluoroacetate or iodine monochloride in a solventsuch as chloroform, acetonitrile, acetic acid or mixtures of solventsthereof at a temperature of 0° to 60° C., followed by normal workupprocedures.

Another coupling reaction, although limited in its applicability, can beused to prepare a compound of Formula (I) where Ar is a dihydroxyphenylas described in synthetic Scheme 3. ##STR44##

Quinone is reacted with a diazonium salt (XXV) prepared from a3-(4-aminophenyl)-2-oxooxazolidin-5-ylmethyl derivative to give anadduct of Formula (XXVI), which can be reduced with a borohydridereducing agent such as sodium borohydride to give a dihydroxy compoundof Formula (XXVII). The hydroxy groups can be converted to thecorresponding ethers using conventional techniques. ##STR45##

Synthetic Scheme 4 is widely applicable to prepare most of the compoundsof Formula (I) provided that there are no active hydrogen atoms (i.e.,no NH, OH or SH) present in Ar as described previously. Compoundscontaining these excluded groups can be prepared via Schemes 1, 3 or 5.A compound of Formula (XXVIII) can be prepared in variety of ways. Forexample, many of such compounds can be prepared by procedures describedin D. J. Byron, G. W. Gray and R. C. Wilson, J. Chem. Soc. (C), 840(1966). A compound of Formula (XXVIII) can be converted to thecorresponding acid chloride followed by reaction with sodium azideaccording to standar organic reaction procedures to a compound ofFormula (XXIX). A compound of Formula (XXIX) is then employed in placeof the compound of Formula (II) in Scheme 1 to give the compound ofFormula (I). ##STR46##

Compounds of Formula (I) which can be prepared according to thesynthetic Scheme 5 are those with Ar groups made up of 5- and 6-memberedring heterocycles as illustrated.

A 3-(4-acetylphenyl)-2-oxooxazolidin-5-yl derivative (XXX) preparedaccording to U.S. Pat. No. 4,705,799 is converted to a compound ofFormula (XXXI) by reacting it with dimethoxydimethylformamide at 100° to120° C. Reaction of a compound of Formula (XXXI) with a variety ofamines give compounds of Formula (I) where Ar is an heteroaromaticmoiety as shown.

Similarly, a bromoacetyl derivative (XXXII) where Q is azide (N₃)obtained by bromination of a compound (XXX) can be reacted with avariety of amides to produce more compounds of Formula (I) where Ar isan heteraromatic moiety. Azides can be reduced to amines as described inU.S. Pat. No. 4,705,799.

Pharmaceutically suitable salts of compounds of Formula (I) can beprepared in a number of ways known in the art. When Q is NH₂,pharmaceutically suitable salts include those resulting from treatmentwith mineral and organic acids such as acetic, hydrochloric, sulfuric,phosphoric, succinic, fumaric, ascorbic, and glutaric acids.

The invention can be further understood by reference to the followingexamples in which parts and percentages are by weight unless otherwiseindicated.

EXAMPLE 1 Preparation of(l)-5-Azidomethyl-3-(4-phenylphenyl)-2-oxazolidinone (I, Ar=C₆ H₅, Q=N₃)Part A: Preparation of (l)-5-Hydroxymethyl-3-(4-phenylphenyl)-2-oxazolidinone (I, Ar=C₆ H₅, Q=OH)

A solution containing 10 g (51.2 mmol) of 4-phenylphenylisocyanate and7.5 g (52.0 mmol) of (l)-glycidyl butyrate in 20 mL of dry xylene wasadded dropwise to 160 mL of boiling dry xylene containing 0.30 g oflithium bromide and 0.75 g of tributylphosphine oxide over a period of30 minutes. The mixture was heated under reflux for 1 hour after theaddition was complete, allowed to cool to room temperature and thesolvent was removed under reduced pressure. The residue was trituratedwith hexane and the resulting solid was dissolved in 150 mL of methanol.To this solution was added 0.7 mL of 25% sodium methoxide in methanol,stirred overnight and the white precipitate formed was collected on afilter to give 13 g (95% theory) of the desired alcohol, mp 236°-240°C., shown to be at least 99% pure by HPLC. The alcohol can be furtherpurified by recrystallization from methanol.

Part B: Preparation of (l)-5-Hydroxymethyl-3-(4-phenylphenyl)-2-oxazolidinone p-toluenesulfonate (I,Ar=C₆ H₅, Q=OTs)

To a solution of 12.94 g (48.05 mmol) of(l)-5-hydroxymethyl-3-(4-phenylphenyl)-2-oxazolidinone in 100 mL of drypyridine was added 10.6 g (15% excess) of p-toluenesulfonyl chloride at0°-5° C., and the mixture was stirred at 10°-15° C. until all of thealcohol was converted to the tosylate (Ts) as shown by HPLC analysis.The mixture was poured into 500 mL of ice water with vigorous stirringand the resulting white precipitate was collected and recrystallizedfrom an ethanol-acetonitrile mixture to give 16.2 g of the tosylate, mp157.5°-158.5° C.

Part C

A mixture of 15.3 g (37.4 mmol) of(l)-5-hydroxymethyl-3-(4-phenylphenyl)-2-oxazolidinonep-toluenesulfonate, 0.2 g of 18-crown-6 and 2.7 g (41.1 mmol, 10%excess) of sodium azide in 60 mL of dry dimethylformamide (DMF) washeated at 70° C. (±5°) for 5 hours and the mixture was poured into 300mL of ice water to give a white precipitate. The precipitate wascollected on a filter to give 10.4 g of the desired azide as a colorlesssolid, mp 163.5°-164.5° C.

EXAMPLE 2 Preparation of(l)-5-Aminomethyl-3-(4-phenylphenyl)-2-oxazolidinone (I, Ar=C₆ H₅,Q=NH₂)

(l)-5-Azidomethyl-3-(4-phenylphenyl)-2-oxazolidinone (10.4 g) suspendedin 200 mL of 95% ethanol was hydrogenated in the presence of 0.7 g ofplatinum oxide under 40-50 psig (2.76×10⁵ -3.45×10⁵ pascals) ofhydrogen. The catalyst was removed by filtration through a celite bed,the bed was washed with tetrahydrofuran (THF) and the combined ethanolfiltrate and THF washings were concentrated under reduced pressure togive 9.2 g of the desired amine as a colorless solid, mp 140°-141° C.

EXAMPLE 3 Preparation of(l)-N-[3-(4-Phenylphenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (I, Ar=C₆H₅, Q=NHCOCH₃)

To a solution containing 9.2 g of(l)-5-aminomethyl-3-(4-phenylphenyl)-2-oxazolidinone and 8 mL oftriethylamine in 200 mL of dry THF was added 3.5 mL of acetyl chloridedissolved in 10 mL of THF dropwise at 0°-10° C. The mixture wasconcentrated under reduced pressure and the residue was triturated withwater to give a solid which was recrystallized from ethanol to give 8.7g of the pure amide as a colorless solid, mp 226°-227° C.

Anal. Calcd for C₁₈ H₁₈ N₂ O₃ : C, 69.66; H, 5.85; N, 9.03. Found: C,69.44; H, 5.94; N, 9.03. C, 69.48; H, 5.85; N, 9.04.

EXAMPLE 4 Preparation of(l)-N-[3-(4-(4'-Acetylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=CH₃ COC₆ H₄, Q=NHCOCH₃)

To 50 g of trifluoromethanesulfonic acid was added 7.5 mL of aceticanhydride dropwise at 0°-5° C. followed by 2.5 g of(l)-N-[3-(4-phenylphenyl)-2-oxooxazolidin-5-ylmethyl]acetamide. Themixture was stirred at room temperature for 3 hours and added dropwiseto 500 mL of ice water with vigorous stirring. The resulting yellowishprecipitate was collected and recrystallized from ethanol to give 2.6 gof the product as a faintly yellowish white solid, mp 261.5°-262.5° C.

Anal. Calcd for C₂₀ H₂₀ N₂ O₄ : C, 68.17; H, 5.72; N, 7.95. Found: C,67.87; H, 5.73; N, 7.92. C, 67.93; H, 5.79; N, 7.84.

By using the procedures described in Examples 1-4, the followingcompounds in Table I were prepared or can be prepared.

                                      TABLE I                                     __________________________________________________________________________     ##STR47##                                                                    Ex.                                                                              X            Y   Q       Isomer                                                                            m.p. (°C.)                             __________________________________________________________________________     1 H            H   N.sub.3 l   163.5-164.5                                    2 H            H   NH.sub.2                                                                              l   140-141                                        3 H            H   NHCOCH.sub.3                                                                          l   226-227                                        4 4'-CH.sub.3 CO                                                                             H   NHCOCH.sub.3                                                                          l   261.5-262.5                                    5 4'-CH.sub.3 CO                                                                             H   NHCO.sub.2 CH.sub.3                                                                   l                                                  6 4'-CH.sub.3 CO                                                                             H   NHSO.sub.2 CH.sub.2 Cl                                                                l                                                  7 4'-CH.sub.3 CH.sub.2 CO                                                                    H   NHCOCH.sub.3                                                                          l   253                                            8 4'-ClCH.sub.2 CO                                                                           H   NHCOCH.sub.3                                                                          l   225                                            9 4'-HO.sub.2 C(CH.sub.2).sub.2 CO                                                           H   NHCOCH.sub.3                                                                          l   240-241                                       10 4'-HO.sub.2 CC(CH.sub.3).sub.2 CH.sub.2 CO                                                 H   NHCOCH.sub.3                                                                          l   222 (dec)                                     11  -n-C.sub.3 H.sub.7                                                                        H    NH.sub.2                                                                             l                                                 12  -n-C.sub.3 H.sub.7                                                                        H   NHCOCH.sub.3                                                                          l                                                 13  -n-C.sub.5 H.sub.11                                                                       H   NHCOCH.sub.3                                                                          l                                                 14 C.sub.2 H.sub.5                                                                            3'-CH.sub.3                                                                       N.sub.3 l                                                 15 C.sub.2 H.sub.5                                                                            3'-CH.sub.3                                                                       NHCOCH.sub.3                                                                          l                                                 16 H            3'-Cl                                                                             NHCOCH.sub.3                                                                          l                                                 17 Cl           3'-CH.sub.3                                                                       NHCOCH.sub.3                                                                          l                                                 18 C.sub.2 H.sub.5                                                                            3'-F                                                                              NHCOCH.sub.3                                                                          l                                                 19 CH.sub.3     3'-F                                                                              NHCOCH.sub.3                                                                          l                                                 __________________________________________________________________________

EXAMPLE 20 Preparation of(l)-N-[3-(4-(4'-Iodophenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=4'-IC₆ H₄, Q=NHCOCH₃)

(l)-N-[3-(4-Phenylphenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (20 g,0.064 mole) in a mixture of trifluoroacetic acid (170 mL) and aceticacid (570 mL) was stirred and heated at 60° C. while adding dropwise asolution of iodine monochloride (139.2 g, 0.86 mole) in acetic acid (225mL) during 6-7 hours. The mixture was stirred at 60° C. overnight,cooled to room temperature and filtered. The resulting filter cake waswashed with ether (to remove excess iodine) and dried to give thedesired iodo compound as a tan solid (20.8 g, 74%) which was 94% pure byHPLC. The filtrate was diluted with water and filtered to separateadditional product 3.4 g. The main fraction was dissolved indimethylformamide (200 mL) and filtered through a shallow bed of Darco®or Celite® (which one?). The filtrate was diluted with water (30 mL) andcooled to give pure product (9.1 g), mp 265°-267° C.

EXAMPLE 21 Preparation of(l)-N-[3-(4-(4'-Formylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=4'-HCOC₆ H₄, Q=NHCOCH₃)

(l)-N-[3-(4-(4'-Iodophenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(4.41 g, 0.01 mole) was refluxed in dry tetrahydrofuran (500 mL) andflushed thoroughly with gaseous CO.Tetrakis(triphenyl-phosphine)palladium(O) (2.35 g, 0.002 mole) was addedand the mixture stirred and heated at 50° C. under slight positivepressure of CO (balloon) while adding tributyltinhydride (2.94 g, 0.01mole) in dry toluene (50 mL) during 6 hours. Heating and stirring undergaseous CO pressure was continued overnight. The reaction mixture wascooled to room temperature, added to petroleum ether (600 mL) andfiltered to separated the desired aldehyde (3.33 g, 97%).Recrystallization from acetonitrile gave pure aldehyde product asfibrous white needles, mp 210° C.

The aldehyde can be readily converted to the corresponding carboxylicacid by oxidation with chromic acid in acetic acid.

EXAMPLE 22 Preparation of(l)-N-[3-(4-(4'-(1-Hydroxyiminoethyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar═4'-CH₃ C(═NOH)C₆ H₄, Q═NHCOCH₃)

A mixture of 2.8 g of(l)-N-[3-(4-(4'-acetylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]-acetamide,5.6 g of hydroxylamine hydrochloride and 11.2 mL of pyridine in 560 mLof absolute ethanol was heated under reflux for 3 hours and the mixturewas allowed to cool to room temperature. The solid formed was collectedand washed with ethanol to give 2.58 g of the desired crude oxime, mp268°-272° C. It can be further purified by recrystallization fromethanol.

EXAMPLE 23 Preparation of Sodium Salt of Succinate Hemiester of(l)-N-[3-(4-(4'-(1-Hydroxyiminoethyl)phenyl)-phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar═4'-CH₃ C(═NOCOCH₂ CH₂ CO₂ Na)C₆ H₄, Q═NHCOCH₃)

To a suspension of 1 g (2.72 mmol) of(l)-N-[3-(4-(4'-(1-hydroxyiminoethyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamidein 30 mL of DMF was added 135 mg (2.8 mmol) of NaH (50% dispersion inmineral oil) and the mixture was heated slowly to 40° C. when it becameclear momentarily, then a massive precipitate formed as it was heated to50° C. for 1 hour. The mixture was allowed to cool to 40° C., and 0.272g (2.72 mmol) of succinic anhydride dissolved in a minimum volume of DMFwas added. The thick white precipitate became opaque and easier to stir.It was heated at 50° C. for 0.5 hour, cooled to room temperature, andthe precipitate was filtered and washed successively with DMF, glyme andether to give 1.05 g of the sodium salt as a colorless white solid, mp297°-300° (dec).

EXAMPLE 24 Preparation of (l)-N-[3-(4-(4'-(1-Carboxymethoxyliminoethyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar═4'-CH₃ C(═NOCH₂ CO₂ H)C₆ H₄, Q═NHCOCH₃)

A mixture containing 1 g of(l)-N-[3-(4-(4'-acetylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide,2 g of carboxymethoxylamine hydrochloride and 4 mL of pyridine in 180 mLof absolute ethanol was heated under reflux for 3 hours. The mixture wasallowed to cool and white precipitate formed was collected and washedwith ethanol to give 0.8 g of the desired product, mp 232° C. (dec). Thesodium salt of the acid can be prepared by treating with aqueous sodiumhydroxide and removing the water.

EXAMPLE 25 Preparation of(l)-N-[3-(4-(4'-Acetylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide4-Methylpiperazinylhydrazone (I, Ar═4'-CH₃ C(═NN(CH₂ CH₂)₂ NCH₃)C₆ H₄,Q═NHCOCH₃)

(l)-N-[3-(4-(4'-Acetylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(2.5 g, 0.0071 mole) and 1-amino-4-methylpiperazine (2.04 g, 0.018 mole)were heated at reflux in dry dioxane (350 mL) with borontrifluorideetherate (0.30 mL) overnight. The solvent was removed on a rotaryevaporator and the product dried (80° C./0.1 mm) to give the titledhydrazine (3.19 g, 100%), mp 200° C. (dec).

EXAMPLE 26 Preparation of(l)-N-[3-(4-(4'-(1-(4-Methylpiperazinylamino)ethyl))phenyl)phenyl-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar═4'-CH₃ CH(NHN(CH₂ CH₂)₂ NCH₃)C₆ H₄, Q═NHCOCH₃)

(l)-N-[3-(4-(4'-Acetylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide4-Methylpiperazinylhydrazone (3.57 g, 0.0079 mole) was heated inmethanol (250 mL) at reflux and then cooled to room temperature. Asolution of NaBH₃ CN (0.5 g, 0.0079 mole) and ZnCl₂ (0.5 g, 0.004 mole)in methanol (20 mL) was added and the mixture stirred at roomtemperature overnight followed by reflux for 0.5 hour. The reactionmixture was added to saturated Na₂ CO₃ (75 mL) and water (200 mL) andextracted with CH₂ Cl₂ /MeOH (9/1, 5×100 mL). The extract was dried(MgSO₄) and the solvent removed on a rotary evaporator to give theproduct (2.91 g, 82%). The product was dissolved in 1N HCl (10 mL) andwater (200 mL) and filtered to separate a solid (0.24 g). The clearfiltrate was divided into two equal parts. One part was made basic withsodium carbonate and extracted with CH₂ Cl₂ /CH₃ OH (9/1, 3×100 mL),dried and the solvent removed to give pure product (1.26 g), mp 120° C.The second portion was freeze dried to give the hydrochloride salt ofthe product (1.2 g), mp 168° C. (dec).

EXAMPLE 27 Preparation of(l)-N-[3-(4-(4'-(1-Hydroxyethyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar═ 4'-CH₃ CH (OH)C₆ H₄, Q═NHCOCH₃)

To a suspension of 0.39 g of(l)-N-[3-(4-(4'-Acetylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]-acetamidein 100 mL of 95% ethanol was added 0.2 g of NaBH₄. The mixture wasslowly heated to its boiling point when the mixture became homogeneous.Heating was continued for 15 minutes, diluted with 100 mL of water,brought it back to boiling, allowed to cool to room temperature andstripped to dryness. The resulting solid was triturated with water togive 0.36 g of white solid, mp 203.5°-208.5° C. It was recrystallizedonce from ethanol to give 0.26 g of the desired alcohol as white solid,mp 207.5°-212.5° C.

Anal. Calcd for C₂₀ H₂₂ N₂ O₄ : 354.1577 (M⁺).

Observed m/e by HRMS: 354.1567.

By using the procedures described in Examples 20-27, the followingcompounds in Table II were prepared or can be prepared.

                                      TABLE II                                    __________________________________________________________________________     ##STR48##                                                                    Ex.                                                                              X                  Q     Isomer                                                                            m.p. (°C.)                             __________________________________________________________________________    20 4'-I               NHCOCH.sub.3                                                                        l   265-267                                       21 4'-HCO             NHCOCH.sub.3                                                                        l   210                                           22 4'-CH.sub.3 C(NOH) NHCOCH.sub.3                                                                        l   268-272                                       23 4'-CH.sub.3 C(NOCOCH.sub.2 CH.sub.2 CO.sub.2 Na)                                                 NHCOCH.sub.3                                                                        l   297-300 (dec)                                 24 4'-CH.sub.3 C(NOCH.sub.2 CO.sub.2 H)                                                             NHCOCH.sub.3                                                                        l   232 (dec)                                     25 4'-CH.sub.3 C(NN(CH.sub.2 CH.sub.2).sub.2 NCH.sub.3)                                             NHCOCH.sub.3                                                                        l   200 (dec)                                     26 4'-CH.sub.3 CH(NHN(CH.sub.2 CH.sub.2).sub.2 NCH.sub.3)                                           NHCOCH.sub.3                                                                        l   168 (dec)                                     27 4'-CH.sub.3 CH(OH) NHCOCH.sub.3                                                                        l   207.5-212.5                                   28 4'-HOCH.sub.2      NHCOCH.sub.3                                                                        l   235                                           29 4'-CH.sub.3 CH(OCOCH.sub.2 CH.sub.2 CO.sub.2 H)                                                  NHCOCH.sub.3                                                                        l   156                                           30 4'-CH.sub.3 CH(OCOCH.sub.2 CH.sub.2 CO.sub.2 Na)                                                 NHCOCH.sub.3                                                                        l                                                 31 4'-CH(NOH)         NHCOCH.sub.3                                                                        l                                                 32 4'-CH(NOCH.sub.2 CO.sub.2 H)                                                                     NHCOCH.sub.3                                                                        l                                                 33 4'-CH(NN(CH.sub.2 CH.sub.2).sub.2 NCH.sub.3)                                                     NHCOCH.sub.3                                                                        l                                                 34 4'-CH.sub.3 CH.sub.2 C(NOH)                                                                      NHCOCH.sub.3                                                                        l                                                 35 4'-CH.sub.3 CH.sub.2 C(NOCOCH.sub.2 CH.sub.2 CO.sub.2 H)                                         NHCOCH.sub.3                                                                        l                                                 36 4'-CH.sub.3 CH.sub.2 CH(OH)                                                                      NHCOCH.sub.3                                                                        l                                                 __________________________________________________________________________

EXAMPLE 37 Preparation of(l)-N-[3-(4-(4'-Cyanophenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar═4'-NCC₆ H₄, Q═NHCOCH₃)

(l)-N-[3-(4-(4'-Iodophenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(20.10 g, 0.046 mole) and cuprous cyanide (16.0 g, 0.16 mole) inN-methylpyrrolidinone (270 mL) were stirred and heated at 125° C. for 24hours. The reaction mixture was cooled to room temperature, poured intoice water, and filtered to separate a brown solid. The solid was addedto a column packed with silica (84 g) and eluted with CHCl₃ /CH₃ OH(9/1, 1000 mL) and methanol (750 mL). The combined eluents wereevaporated to dryness on a rotary evaporator to give the product (12.6g, 81%) which was 96% pure by HPLC. This material was recrystallizedfrom chloroform to give the pure cyano compound, mp 208°-209° C.

Anal calcd: C,68.05; H,5.11; N,12.53. Found: C,68.14; H,5.14; N,12.40.C,68.05; H,5.06; N,12.49.

HRMS m/e calcd: 335.1270, measured 335.1268.

EXAMPLE 38 Preparation of(l)-N-[3-(4-(4'-(5-Tetrazolyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar═4'-N₄ CC₆ H₄, Q═NHCOCH₃

(l)-N-[3-(4-(4'-Cyanophenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(2.68 g, 0.0080 mole) was heated in dimethylformamide (25 mL) withtrimethylsilyl azide (1.89 g, 0.016 mole) at 140° C. for 5.5 hours. Moreazide (1.8 g, 0.016 mole) was added and heating at 140° C. was continuedfor a total of 45 hours. The reaction mixture was poured onto ice andcentrifuged to separate a brown solid which was washed with water anddried (2.71 g, 90%). The product was purified by chromatography onsilica and eluted with CHCl₃ /CH₃ OH (9/1) and then with methanol. Themethanol fraction proved to be the pure product, mp 244° C. (dec). Thesodium salt of the product can be prepared by treating with aqueoussodium hydroxide and removing the water.

EXAMPLE 39 Preparation of(l)-N-[3-(4-(4'-((N,N-Methylethylamino)methyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar═4'-CH₃ CH₂ N(CH₃ CH₂ C₆ H₄, Q═NHCOCH₃)

(l)-N-[3-(4-(4'-Formylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(1.7 g, 0.005 mole) and ethylmethylamine (1.48 g, 0.025 mol) were heatedat reflux in methanol (170 mL). The mixture was cooled to 25° C. and asolution of sodium cyanoborohydride (0.315 g, 0.005 mole) in methanol(12.1 mL) was added and the mixture stirred at room temperatureovernight. The reaction mixture was added to saturated sodiumbicarbonate (25 mL) and water (100 mL) and extracted with CH₂ Cl₂ /MeOH(9/1, 3×100 mL). The extract was dried (MgSO₄), filtered and the solventremoved on a rotary evaporator to give a white solid which wastriturated with ether and dried to give the product (1.65 g, 86%). Theproduct was dissolved in 1N HCl (10 mL) and water (150 mL) to give aclear solution. One half of this solution was made basic with sodiumcarbonate and extracted with CH₂ Cl₂ /CH₃ OH (9/1, 3×100 mL). Theextract was dried (MgSO₄), filtered and the solvent removed to give pureamine (0.84 g), mp 162°-164° C. The residual acidic solution was freezedried to give the hydrochloride salt of the amine (0.32 g), mp 145°-147°C. (dec).

With primary amines, the reaction may stop at the imine stage when thereduction is carried out at room temperature. Refluxing the reactionmixture for 1-3 hours with a small excess of NaBH₃ CN or NaBH₄ completesthe reduction.

Reductive alkylation of ketones frequently fails with NaBH₃ CN/ZnCl₂ butthe intermediate hydrazone can be prepared and reduced as describedpreviously in Example 27.

By using the procedures described in Examples 37-39, the followingcompounds in Table III were prepared.

                                      TABLE III                                   __________________________________________________________________________     ##STR49##                                                                    Ex. X               Q      Isomer                                                                             m.p. (°C.)                             __________________________________________________________________________    37  4'-NC           NHCOCH.sub.3                                                                         l    208-209                                       38  4'-N.sub.4 C    NHCOCH.sub.3                                                                         l    244 (dec)                                     39  4'-CH.sub.3 CH.sub.2 N(CH.sub.3)CH.sub.2                                                      NHCOCH.sub.3                                                                         l    162-164                                       40  4'-CH.sub.3 NHCH.sub.2                                                                        NHCOCH.sub.3                                                                         l    197 (dec)                                     41  4'-(CH.sub.3).sub.2 NCH.sub.2                                                                 NHCOCH.sub.3                                                                         l    197                                           42  4'-CH.sub.3 CH.sub.2 NHCH.sub.2                                                               NHCOCH.sub.3                                                                         l    180                                           43  4'-(CH.sub.3 CH.sub.2).sub.2 NCH.sub.2                                                        NHCOCH.sub.3                                                                         l    137 (dec)                                     44  4'-( -n-Pr).sub.2 NCH.sub.2                                                                   NHCOCH.sub.3                                                                         l    128                                           45  4'- -n-C.sub.4 H.sub.9 NHCH.sub.2                                                             NHCOCH.sub.3                                                                         l    200                                           46  4'-( -n-C.sub.4 H.sub.9).sub.2 NCH.sub.2                                                      NHCOCH.sub.3                                                                         l    107                                           47  4'-( -n-C.sub.5 H.sub. 11).sub.2 NCH.sub.2                                                    NHCOCH.sub.3                                                                         l    142                                           48  4'- -n-C.sub.8 H.sub.17 NCH                                                                   NHCOCH.sub.3                                                                         l    210                                           49  4'- -n-C.sub.8 H.sub.17 NHCH.sub.2                                                            NHCOCH.sub.3                                                                         l    209                                           50  4'-(HOCH.sub.2 CH.sub.2).sub.2 NCH.sub.2                                                      NHCOCH.sub.3                                                                         l    123                                           51  4'-CH.sub.3 N(CH.sub.2 CH.sub.2).sub.2 NNHCH.sub.2                                            NHCOCH.sub.3                                                                         l    194 (dec)                                     52                                                                                 ##STR50##      NHCOCH.sub.3                                                                         l    100                                           53                                                                                 ##STR51##      NHCOCH.sub.3                                                                         l                                                  54  4'-CH.sub.3 OCH.sub.2 CH.sub.2 CH.sub.2 NHCH.sub.2                                            NHCOCH.sub.3                                                                         l                                                  55  4'-(CH.sub.3).sub.2 NCH.sub.2 CH.sub.2 NHCH.sub.2                                             NHCOCH.sub.3                                                                         l                                                  56                                                                                 ##STR52##      NHCOCH.sub.3                                                                         l                                                  __________________________________________________________________________

EXAMPLE 57 Preparation of(l)-N-[3-(4-(4'-(3-N,N-dimethylaminopropionyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=4'-(CH₃)₂ NCH₂ CH₂ COC₆ H₄, Q=NHCOCH₃)

N,N,N',N'-Tetramethyldiaminomethane (0.29 g, 0.0028 mole) was addeddropwise to trifluoroacetic acid (5 mL) cooled at -10° C. and stirredfor 10 minutes.(l)-N-[3-(4-(4'-Acetylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(1.0 g, 0.0028 mol) was added slowly as a solid at -10° C. The coolingbath was removed and the mixture stirred while warming slowly to roomtemperature. The reaction temperature was then gradually raised to60°-65° C. and heated at this temperature overnight. The reactionmixture was added dropwise to saturated sodium carbonate (50 mL) cooledin an ice bath. The resulting mixture was filtered and the yellow solidwashed with water and dried to give the product, 1.12 g, 97%, mp192°-194° C.

A portion of the product (0.5 g) was dissolved in 1N HCl (10 mL) andwater (50 mL), filtered and the clear yellow solution freeze dried togive hydrochloride salt of the ketoamine (0.4 g), mp 150° C. gassing,195° C. (dec).

When the Mannich resection was carried out usingbis-(N-methylpiperidinyl)methane and propionyl derivative (I, Ar=4'-CH₃CH₂ COC₆ H₄ --, B=NHCOCH₃), an elimination product (I, Ar=4'-CH₂═C(CH₃)COC₆ H₄ --, Q=NHCOCH₃) was also obtained (Example 63).

EXAMPLE 58 Preparation of(l)-N-[3-(4-(4'-(3-N,N-Dimethylamino-1-hydroxypropyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=4'-(CH₃)₂ NCH₂ CH₂ CH(OH)C₆ H₄, Q=NHCOCH₃)

(l)-N-[3-(4-(4'-3-N,N-Dimethylaminopropionyl)phenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(3.14 g, 0.0077 mole) in acetic acid (35 mL) was stirred with NaBH₃ CN(1.93 g) at room temperature overnight. The solution was added dropwiseto saturated sodium carbonate (400 mL) and the pH adjusted to 9-10. Themixture was extracted with CH₂ Cl₂ /CH₃ OH, (9/1, 4×150 mL). The extractwas dried and the solvent removed to give the crude reduced amine (2.74g, 87%). The compound was chromatographed on silica gel by eluting withCHCl₃ /CH₃ OH (9/1) to give pure amine, mp 194° C. A portion of theamine was dissolved in dilute HCl and freeze dried to give thehydrochloride salt.

By using the procedures described in Examples 57 and 58, the followingcompounds in Table IV were prepared or can be prepared.

                                      TABLE IV                                    __________________________________________________________________________     ##STR53##                                                                    Ex.                                                                              X                     Q     Isomer                                                                            m.p. (°C.)                          __________________________________________________________________________    57 4'-(CH.sub.3).sub.2 NCH.sub.2 CH.sub.2 CO                                                           NHCOCH.sub.3                                                                        l   192-194                                    58 4'-(CH.sub.3).sub.2 NCH.sub.2 CH.sub.2 CH(OH)                                                       NHCOCH.sub.3                                                                        l   194                                        59 4'-O(CH.sub.2 CH.sub.2).sub.2 NCH.sub.2 CH.sub.2 CH(OH)                                             NHCOCH.sub.3                                                                        l   165                                        60 4'-CH.sub.3 N(CH.sub.2 CH.sub.2).sub.2 NCH.sub.2 CH.sub.2 CO                                        NHCOCH.sub.3                                                                        l   221                                        61 4'-CH.sub.3 N(CH.sub.2 CH.sub.2).sub.2 NCH.sub.2 CH.sub.2 CH(OH)                                    NHCOCH.sub.3                                                                        l   151 (dec)                                  62 4'-CH.sub.3 N(CH.sub.2 CH.sub.2).sub.2 NCH.sub.2 CH(CH.sub.3)CO                                     NHCOCH.sub.3                                                                        l   105                                        63 4'-CH.sub.2C(CH.sub.3)CO                                                                            NHCOCH.sub.3                                                                        l   216                                        64 4'-CH.sub.3 N(CH.sub.2 CH.sub.2).sub.2 NCH.sub.2 CH(CH.sub.3)CH(OH)                                 NHCOCH.sub.3                                                                        l   180                                        __________________________________________________________________________

EXAMPLE 65 Preparation of(l)-N-[3-(4-(3'-Methylsulfenylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=3'-CH₃ SOC₆ H₄, Q=NHCOCH₃)

To a mixture containing 23.4 g (0.1 mol) of(l)-N-(3-phenyl-2-oxooxazolidin-5-ylmethyl)acetamide and 29 g (0.13 mol)of silver trifluoroacetate, 300 mL of acetonitrile and 200 mL ofchloroform was added 27 g of iodine in one portion and allowed to stirat room temperature overnight. The mixture was filtered and the filtratewas concentrated under reduced pressure to give a brown solid which wastriturated with distilled water, filtered and washed thoroughly withdistilled water. The resulting solid was recrystallized from 200 mL ofacetonitrile (activated charcoal used) to give 27.5 g (77%) of(l)-N-[3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (XXIV) as acolorless crystalline solid, m.p. 194.5°-195.5° C.

A Grignard reagent was prepared from 25 g (0.123 mol) ofm-bromothioanisole and 3.59 g (0.148 mol) of magnesium in 125 mL oftetrahydrofuran. This solution was added to 56.8 mL (0.246 mol) oftriisopropylborate in tetrahydrofuran at -70° C. The borate ester washydrolyzed with 10% sodium hydroxide solution, then acidified to givethe boronic acid. Recrystallization from water gave 11.0 g of theboronic acid, mp 162°-163° C.

A mixture of 2.5 g (0.015 mol) of the above boronic acid in 40 mL ofDMF, 4.2 mL of triethylamine, 3.6 g of(l)-N-[3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide, 0.2 g oftri-2-tolylphosphine and 80 mg of palladium acetate was subjected tofour "Firestone" cycles. The homogenous solution was held at 100° C.under nitrogen for 72 hours, cooled, and filtered. The DMF was removedat 70° C. (0.5 mm Hg) and the residue dissolved in methylene chlorideand washed with 10% ammonium hydroxide solution, dried over magnesiumsulfate and solvent evaporated to give 2.31 g of crude material whichwas chromatographed on 70 g of silica gel with an eluent of methylenechlorideacetone to give 1.24 g of material consistent with product.Recrystallization from acetonitrile gave 0.8 g of pure(l)-N-[3-(4-(3'-methylthiophenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide.

A mixture of 0.51 g (0.0014 mol) of the sulfide in 155 mL of chloroformwas held at reflux to dissolve the solid, then cooled to -30° C., and asolution of 0.30 g (0.0014 mol) of 82% m-chloroperbenzoic acid in 15 mLof methylene chloride was added at -30° C., then allowed to warm to -20°C. After addition of 0.1 mL of dimethylsulfide, the mixture was warmedto 20° C. and the solvent removed. The residue was dissolved inchloroform and washed with saturated sodium bicarbonate solution, driedover potassium carbonate and solvent evaporated. The residue waschromatographed on 25 g of silica gel with methylene chloride-acetone asthe eluent. The product was dissolved in water, filtered (0.2 micronmembrane filter) and the water removed. The residue was recrystallizedfrom isopropanol to give 180 mg of the sulfoxide, mp 162°-167° C. ¹H-NMR (d₆ -DMSO) δ8.27 (m,1H), 7.93 (s,1H), 7.80 (m,3H), 7.67 (m,4H),4.73 (m,1H), 4.20 (t,1H), 3.80 (t,1H), 3.45 (m,2H), 2.80 (s,3H), 1.83(s,3H); IR (KBr): 3280, 1750; 1665, 1610, 1520, 1050 cm⁻¹.

The sulfoxide can further oxidize to sulfone by reacting with excessMCPBA in chloroform under reflux for 3 hours.

EXAMPLE 66 Preparation of(l)-N-[3-(4-(4'-N,N-Dimethylaminoethyloxyphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=4'-(CH₃)₂ NCH₂ CH₂ OC₆ H₄, Q=NHCOCH₃)

A freshly prepared solution of 4-benzyloxyphenyl magnesium bromide (from21.05 g of 4-benzyloxybromobenzene and 2.2 g of magnesium metal) intetrahydrofuran (80 mL) was added carefully to a stirred solution offreshly fused zinc chloride (17.14 g) in tetrahydrofuran maintained at0°-5° C. The resulting mixture was stirred at room temperature for 30minutes and then treated with(l)-N-[3-(4-iodophenyl)-2-oxooxazolidin-5-yl]methylacetamide (14.4 g),added in one lot, followed by the addition ofbis(triphenylphosphine)nickel(II) chloride (4.0 g). The mixture wasstirred at room temperature for 90 minutes and then poured into anexcess of ice and 1N HCl and the solid that separated filtered off,washed with water, boiled with tetrahydrofuran and filtered. The solidwas washed with a small quantity of tetrahydrofuran followed by hexanesand air-dried to yield 9.72 g of(l)-N-[3-(4-(4'-benzyloxyphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamideas a colorless solid, mp 235°-237° C. (dec). It was pure enough to beused in the next step. An analytical sample was prepared byrecrystallizing a small quantity of the product from acetic acid, mp243°-245° C. (dec).

A suspension of the benzyloxy compound (6.74 g) in a solution ofhydrogen bromide in acetic acid (72 mL; 30.32%) was stirred and heatedunder reflux for 10 to 15 minutes, cooled and filtered. The colorlesssolid was washed with ether and air-dried to yield(l)-N-[3-(4-(4'-hydroxyphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(4.03 g), mp 280°-281° C. (dec).

Sodium hydride (0.5 g; 50% oil dispersion) was added in small portionsto a stirred solution of the phenolic compound (3.26 g) in warmdimethylformamide (75 mL) and, after the addition was complete, themixture was stirred at room temperature for 15 minutes and then treatedwith a freshly prepared solution of 2-dimethylaminoethyl chloride (from6.0 g of the hydrochloride and aq NaHCO₃) in benzene (30 mL) added inone lot. The resulting mixture was stirred and heated at 90°-100° C.overnight and then stripped of the solvents under reduced pressure. Theresidue was triturated with water and filtered. The solid was dissolvedin requisite volume of methylene chloride and the solution extractedtwice with 1N HCl (50 mL each time). The combined acid extracts werefiltered to remove traces of undissolved material and the filtratecooled and basified with conc. ammonium hydroxide. The mixture wasextracted twice with methylene chloride and the combined methylenechloride extracts were washed with H₂ O, dried over MgSO₄ and strippedof the solvent under reduced pressure to yield a solid which wasrecrystallized from isopropanol to furnish 1.4 g of(l)-N-[3-(4-(4'-N,N-Dimethylaminoethyloxyphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamideas a colorless solid, mp 202°-204° C.

EXAMPLE 67 Preparation of(l)-N-[3-(4-4'-Methylthiophenyl)-phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=4'-CH₃ SC₆ H₄ --, Q=NHCOCH₃)

A Grignard reagent was prepared from 12.2 g (0.06 mol) ofp-bromothioanisole and 1.7 g (0.07 mol) of magnesium in 70 mL oftetrahydrofuran. This solution was added to 22.7 mL oftriisopropylborate in tetrahydrofuran at -70° C. The borate ester washydrolyzed with 150 mL of 1N sodium hydroxide solution and most of thetetrahydrofuran from the mixture was removed under reduced pressure.Acidification of the basic solution with 10% hydrochloric acid gave 9.28g of the crude boronic acid. Recrystallization from water gave 3.8 g ofpure p-methylmercaptophenylboronic acid as a colorless, crystallinesolid, m.p. 211.5°-212° C.

A mixture of 2.52 g (0.015 mol) of the above boronic acid in 40 mL ofDMF, 4.2 mL of triethylamine, 3.6 g of(l)-N-[3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide, 0.2 g oftri-2-tolylphosphine and 80 mg of palladium acetate under nitrogenatmosphere was heated at 100° C. for 72 hrs., cooled, and diluted with40 mL of ether. The solid precipitate formed was filtered, washedsuccessively with ether, water, sodium bicarbonate and water to give acrude product. The crude product was recrystallized once from ethanol togive 1.3 g of pure(l)-N-[3-(4-(4'-methylthiophenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide,m.p. 244.5°-246.5° C. HRMS: Calcd. 356.1195; Measured, 356.1168.

EXAMPLE 68 Preparation of(l)-N-[3-(4-(4'-Methylsulfenylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=4'-CH₃ SOC₆ H₄ -, Q=NHCOCH₃)

A mixture of 0.6 g (1.68 mmol) of the sulfide of Example 67 in 250 mL ofchloroform was heated to dissolve the solid, then cooled to -30° C., and0.36 (1.68 mmol) of 82% m-chloroperbenzoic acid was added at -30° C.,then allowed to slowly warm to -10°. Trace of insoluble material wasremoved by filtration and the filtrate was diluted with ether toprecipitate 0.59 g of the sulfoxide, m.p. 217°-219° C. The product wasshown to be at least 99% pure by hplc. An nmr (CDCl₃) showed absence ofany sulfone resonance. HRMS: Calcd. 372.1144; Measured, 372.1156.

EXAMPLE 69 Preparation of(l)-N-[3-(4-(4'-Methylsulfonylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=4'-CH₃ SO₂ C₆ H₄ -, Q=NHCOCH₃)

A mixture of 0.4 g (1.1 mmol) of the sulfide of Example 67 and 0.53 g(2.45 mmol) of 82% m-chloroperbenzoic acid in 200 mL of chloroform washeated under reflux for 2.5 h. The mixture was cooled and diluted withether to precipitate the desired sulfone, 0.4 g, m.p. 259°-260.5° C.dec. The product was shown to be homogeneous by hplc. HRMS: Calcd.338.1089; Measured, 338.1126.

By using the procedures described in Examples 65-69, the followingcompounds in Table V were prepared or can be prepared.

                                      TABLE V                                     __________________________________________________________________________     ##STR54##                                                                    Ex.                                                                              X            Y    Q     Isomer                                                                            m.p. (°C.)                              __________________________________________________________________________    65 3'-CH.sub.3 SO                                                                             H    NHCOCH.sub.3                                                                        l   162-167                                        66 4'-(CH.sub.3).sub.2 NCH.sub.2 CH.sub.2 O                                                   H    NHCOCH.sub.3                                                                        l   202-204                                        67 4'-CH.sub.3 S                                                                              H    NHCOCH.sub.3                                                                        l   244.5-246.5                                    68 4'-CH.sub.3 SO                                                                             H    NHCOCH.sub.3                                                                        l   217-219                                        69 4'-CH.sub.3 SO.sub.2                                                                       H    NHCOCH.sub.3                                                                        l     259-260.5 (dec)                              70 3'-CH.sub.3 CH.sub.2                                                                       H    NHCOCH.sub.3                                                                        l   121-122                                        71 2'-CH.sub.3  H    NHCOCH.sub.3                                                                        l   181-183                                        72 3'-HCO       H    NHCOCH.sub.3                                                                        l   146-147                                        73 3'-NH.sub.2  H    NHCOCH.sub.3                                                                        l   220-221                                        74 3'-(CH.sub.3).sub.2 N                                                                      H    NHCOCH.sub.3                                                                        l     163-163.5                                    75 4'-CH.sub.3 O                                                                              H    NHCOCH.sub.3                                                                        l   239- 241 (dec)                                 76 4'-(CH.sub.3).sub.2 N(CH.sub.2).sub.3 O                                                    H    NHCOCH.sub.3                                                                        l   191-193                                        77 4'-C.sub.6 H.sub.5 CH.sub.2 OCOCH.sub.2 O                                                  H    NHCOCH.sub.3                                                                        l   186-187                                        78 4'-HO.sub.2 CCH.sub.2 O                                                                    H    NHCOCH.sub.3                                                                        l   228-230 (dec)                                  79 4'-F         H    NHCOCH.sub.3                                                                        l   229-230 (dec)                                  80 4'-Cl        H    NHCOCH.sub.3                                                                        l   249-250 (dec)                                  81 4'-CH.sub.3  5'-CH.sub.3                                                                        NHCOCH.sub.3                                                                        l   168-169                                        82 3'-CH.sub.3  5'-CH.sub.3                                                                        NHCOCH.sub.3                                                                        l   106-107                                        83 4'-F         5'-F NHCOCH.sub.3                                                                        l   201.5-203                                      84 3'-F         5'-F NHCOCH.sub.3                                                                        l     204-204.5                                    __________________________________________________________________________

EXAMPLE 85 Preparation of(l)-N-[3-(4-(4-Pyridyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (I,Ar=4'-NC₅ H₄, Q=NHCOCH₃

To a stirred solution of 75 g (0.386 mol) of 4-bromopyridinehydrochloride in 400 mL of ether and 200 mL of water (2 layer system)was added 40 g of sodium carbonate (0.38 mol) in several portions. Thewater was separated, the ether layer was washed once with brine, dried(MgSO₄) and most of the solvent was removed under reduced pressure. Assoon as the vacuum started to improve indicating that most of the etherwas removed, 200 mL of fresh anhydrous ether was added and the solventwas again removed. This process was repeated once more to minimize anymoisture present. To the residue still containing small amount of etherwas added 750 mL of ether immediately. The solution was cooled to -78°C., and 185 mL (0.462 mol, 20% excess) of 2.5N n-butyllithium (inhexane) was added at such a rate that the temperature of the reactionmixture remained below -65° C. (˜20 min). When the temperature returnedto below -70°, 92.2 g (0.463 mol) of trimethyltin chloride dissolved in200 mL of ether was added at below -65° C. When the addition wascomplete, it was stirred at -75° C. for 0.5 hour, and then the coolingbath was removed to allow the temperature of the reaction to slowlyrise. When the temperature of the reaction reached -20° C., 10 mL ofmethanol followed by 200 mL of water were added and the mixture wasallowed to come to room temperature. The ether layer was washed oncewith brine, dried (MgSO₄) and the solvent was evaporated under reducedpressure to give 114 g of a light tan liquid. The pure product wasisolated by distillation through a 30 cm Vigreux colum, bp 40°-42° C.(0.1 mm), [bp 32°-34° C. (0.07 mm)]. n-Butyltrimethyltin, a by-product,distills at below room temperature at this pressure and separates wellby distillation through the 30 cm Vigreux column.

A mixture containing 74.5 g (0.207 mol) of(l)-N-[3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide, 60 g(0.248 mol) of 4-pyridyltrimethyltin, 23 g (0.033 mol) of freshlyprepared bis(triphenylphosphine)palladium(II) chloride and 71 mL oftriethylamine in 1300 mL of dry dimethyformamide (DMF) was heated at50°-60° C. until all of the iodophenyloxazolidinone is used up (24-48hours) as monitored by HPLC. The insoluble catalyst was removed byfiltration through a bed of Celite® and the volatile material and all ofthe solvent (DMF) from the filtrate was removed under reduced pressure(<40° C.). The resulting oil was taken up in 500 mL of chloroform anddiluted with 1.5 L of ether to give a tan precipitate. The precipitatewas filtered and dried under a stream of nitrogen, digested with 1 L of1N HCl, filtered to remove insoluble material and neutralized to pH of 8using conc. ammonium hydroxide at 10°-20° C. The off-white precipitatewas collected on a filter, dissolved in 400 mL of hot 95% ethanol,treated with charcoal, and diluted with 700 mL of water. The solutionwas concentrated under reduced pressure to remove most of the ethanol togive an off-white precipitate. The precipitate was collected on a filterand washed with a small amount of ice water and dried to give 26 g(40.3% theory) of the product, mp 188°-190° C. Several other runsconducted under the same conditions gave products in 40-45% yields. Thematerial can be further purified by recrystallization from absoluteethanol, or repeating the work-up procedure to give analytically puresample of(l)-N-[3-(4-(4-pyridyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide as acolorless white solid, mp 191°-192° C.

Anal. Calcd for C₁₇ H₁₇ N₃ O₃ : C, 65.58; H, 5.50; N, 13.50; Found: C,65.33; H, 5.67; N, 13.37. C, 65.35; H, 5.53; N, 13.38.

Following a procedure similar to the one described in Example 65, amineoxide derivatives of the pyridyl compounds were prepared by treatingwith excess MCPBA.

l-N-[3-(4-Tri-n-butylstannylphenyl)-2-oxooxazolidin-5-yl-methyl]acetamidewas prepared as follows.

To a mixture of 7.0 mL of hexabutylditin, 3.60 g of(l)-N-[3-(4-iodophenyl)-2-oxooxazolidin-5-ylmethyl]-acetamide and 25 mLof DMF under nitrogen, which had been subjected to several Firestonecycles to remove oxygen, was added 0.16 g of (PhCN)₂ PdCl₂ with stirringand the mixture was stirred at 70° C. overnight. The mixture was pouredinto 500 mL of water and extracted with ethyl acetate, which was dried(MgSO₄), filtered through a Celite® pad to remove both Pd and the MgSO₄,and evaporated in vacuo. The mixture was chromatographed on silica withchloroform to give the pure(l)-N-[3-(4-tri-n-butylstannylphenyl)-2-oxooxazolidin-5-ylmethyl]acetamidefree from tributyltin iodide by-product as a contaminant. Isolated was3.21 g.

By using the procedures described in Example 85, the following compoundsin Table VI were prepared or can be prepared.

                                      TABLE VI                                    __________________________________________________________________________     ##STR55##                                                                    Ex.  Ar            Q      Isomer                                                                             m.p. (°C.)                              __________________________________________________________________________    85   4'-NC.sub.5 H.sub.4                                                                         NHCOCH.sub.3                                                                         l    191-192                                        86   2'-NC.sub.5 H.sub.4                                                                         NHCOCH.sub.3                                                                         l    170-173                                        87   2'-ONC.sub.5 H.sub.4                                                                        NHCOCH.sub.3                                                                         l    110 (dec)                                      88   3'-NC.sub.5 H.sub.4                                                                         NHCOCH.sub.3                                                                         l    183-185                                        89   3'-ONC.sub.5 H.sub.4                                                                        NHCOCH.sub.3                                                                         l    220 (dec)                                      90   4'-ONC.sub.4 H.sub.4                                                                        NHCOCH.sub.3                                                                         l                                                   91   4'-ClC.sub.6 H.sub.4                                                                        NHCOCH.sub.3                                                                         l    249-250                                        92                                                                                  ##STR56##    NHCOCH.sub.3                                                                         l    221-222 (dec)                                  93                                                                                  ##STR57##    NHCOCH.sub.3                                                                         l    196 (dec)                                      94                                                                                  ##STR58##    NHCOCH.sub.3                                                                         l                                                   95                                                                                  ##STR59##    NHCOCH.sub.3                                                                         dl                                                  96                                                                                  ##STR60##    NHCOCH.sub.3                                                                         dl                                                  97                                                                                  ##STR61##    NHCOCH.sub.2 Cl                                                                      l                                                   98                                                                                  ##STR62##    NHSOCH.sub.3                                                                         l                                                   99                                                                                  ##STR63##    NHCOC.sub.3 H.sub.7                                                                  l                                                   100                                                                                 ##STR64##    NHSO.sub.2 C.sub.2 H.sub.5                                                           l                                                   101                                                                                 ##STR65##    NHCOCH.sub.3                                                                         l                                                   102                                                                                 ##STR66##    N.sub.3                                                                              l                                                   103                                                                                 ##STR67##    NH.sub.2                                                                             l                                                   104                                                                                 ##STR68##    NHCOCH.sub.3                                                                         l                                                   105                                                                                 ##STR69##    NHCOCH.sub.3                                                                         l                                                   106                                                                                 ##STR70##    NHCOCH.sub.3                                                                         l                                                   107                                                                                 ##STR71##    NHCOCH.sub.3                                                                         l                                                   108                                                                                 ##STR72##    NHCOCH.sub.3                                                                         l                                                   109                                                                                 ##STR73##    NHCOCH.sub.3                                                                         l                                                   110                                                                                 ##STR74##    NHCOCH.sub.3                                                                         l                                                   111                                                                                 ##STR75##    NHCOCH.sub.3                                                                         l                                                   112                                                                                 ##STR76##    NHCOCH.sub.3                                                                         l                                                   __________________________________________________________________________

EXAMPLE 113 Preparation of(l)-N-[3-(4-(2',5'-Dihydroxyphenyl)-phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I,Ar=2',5'-(HO)₂ C₆ H₄, Q=NHCOCH₃)

(l)-N-[3-(4-Nitrophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide wasprepared according to the procedures previously described in U.S. Pat.No. 4,705,799. The nitro compound was reduced to the corresponding aminoderivative by catalytic hydrogenation in 95% ethanol in the presence ofplatinum oxide under 40 psig of hydrogen pressure.

To a mixture containing 1 g (4 mmol) of(l)-N-[3-(4-aminophenyl)-2-oxooxazolidin-5-ylmethyl]acetamide, 1 mL of28% HCl and 4 g of ice was added a solution of 0.28 g of sodium nitritein 1 mL of water dropwise at 0°-5° C. After the addition was complete,the mixture was tested with starch/iodide paper to insure the reactionwas complete. The mixture after being made neutral (pH 6-7) by cautionsaddition of sodium carbonate dropwise to a solution of 0.65 g (50%excess) of benzoquinone dissolved in a minimum amount (˜15 mL) of 95%ethanol with vigorous stirring at 10°-15° C. The mixture was allowed tocome to room temperature, stirred for 1 hour and diluted with 200 mL ofwater. The desired benzoquinone attached phenyloxazolidinone wasobtained as a brick colored solid, 0.95 g, mp 218°-219.5° C. It wasrecrystallized once from acetonitrile to give 0.4 g of the pure quinonederivative as a golden orange solid, mp 235°-236° C.

To the orange solid (1.6 g, 4.7 mmol) suspended in 45 mL of 95% ethanolwas added 0.5 g of sodium borohydride. A slight exotherm was noted andthe mixture became homogeneous in 10 minutes. Water (50 mL) was addedand the mixture was warmed to 50° C. After allowing to cool, most of theethanol was removed under reduced pressure and the resulting aqueoussolution was made acidic (pH 1) with 6M HCl to precipitate the product.The product was obtained as a light grayish purple solid, 1.03 g, mp227°-228.5° C.

EXAMPLE 114 Preparation of(l)-N-[3-(4-(4'-Ethylphenyl)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar=4'-CH₃ CH₂ C₆ H₄, Q=NHCOCH₃)

To 4'-ethylbiphenylcarboxylic acid (20 mmol) dissolved in 50 mL dry DMFwas added 25 mmol of triethylamine and the mixture was cooled in an icebath, added 38.5 mmol of methyl chloroformate dropwise at 0°-5° C., andthen stirred at room temperature for 15 minutes. The mixture was cooledto 0° C. again, and a cold solution of 38.5 mmol of sodium azidedissolved in a minimum amount of water (<8 mL) was added as rapidly aspossible (in one portion if possible) at <5° C. The reaction mixture wasstirred at 0° C. for 1 hour and poured into 500 mL of ice-water. Theresulting precipitate was filtered while still cold (<10 min), washedwith cold water and dried under a stream of nitrogen to give the crude4'-ethylbiphenylcarbonyl azide. The azide was used in place of4'-ethylbiphenylisocyanate for the subsequent reactions according to theprocedures exactly paralleling those described previously for Examples 1through 3 to give the desired product as a colorless solid, mp 223°-224°C.

By using the procedures described in Examples 113 and 114, the followingcompounds in Table VII were prepared or can be prepared.

                  TABLE VII                                                       ______________________________________                                         ##STR77##                                                                    Ex.  Ar             Q          Isomer                                                                              m.p. (°C.)                        ______________________________________                                        113  2',5'-diOHC.sub.6 H.sub.3                                                                    NHCOCH.sub.3                                                                             l       227-228.5                              114  4'-C.sub.2 H.sub.5 C.sub.6 H.sub.4                                                           NHCOCH.sub.3                                                                             l     223-224                                  115  4'-(CH.sub.3).sub.2 NC.sub.6 H.sub.4                                                         NHCOCH.sub.3                                                                             dl                                             116  4'-(CH.sub.3).sub.2 N(O)C.sub.6 H.sub.4                                                      NHCOCH.sub.3                                                                             dl    125-127                                  117  4'-(9-fluorinon-2-yl)                                                                        NHCOCH.sub.3                                                                             l     237.5-238.5                              118  4'-(9-fluorinol-2-yl)                                                                        NHCOCH.sub.3                                                                             l     214-221                                  119  3'-O.sub.2 NC.sub.6 H.sub.4                                                                  NHCOCH.sub.3                                                                             l     140-141                                  120                                                                                 ##STR78##     NHCOCH.sub.3                                                                             dl                                             121                                                                                 ##STR79##     NHCOCH.sub.3                                                                             dl                                             122                                                                                 ##STR80##     NHCOCH.sub.3                                                                             l                                              123                                                                                 ##STR81##     NHCOCH.sub.3                                                                             l                                              124                                                                                 ##STR82##     NHCOCH.sub.3                                                                             l                                              125                                                                                 ##STR83##     NHCOCH.sub.3                                                                             l                                              126                                                                                 ##STR84##     NHCOCH.sub.3                                                                             l                                              127                                                                                 ##STR85##     NHCOCH.sub.3                                                                             l                                              128                                                                                 ##STR86##     NHCOCH.sub.3                                                                             l                                              129                                                                                 ##STR87##     NHCOCH.sub.3                                                                             l     209-211                                  ______________________________________                                    

EXAMPLE 130 Preparation of(l)-N-[3-[4-(5-Isoxazolyl)phenyl]-2-oxooxazolidin-5-ylmethyl]acetamide(I, Ar═5-isoxazolyl, Q=NHCOCH₃)

A mixture of(l)-N-[3-(4-acetylphenyl)-2-oxooxazolidin-5-ylmethyl]acetamide (500 mg,1.8 mmol) in 2 mL of dimethoxyformamide was heated at 110° C. overnight(16 hours). Excess dimethoxyformamide was removed in vacuo and theresidue was purified by flash column chromatography to give 328 mg (55%)of(l)-N-[3-(4-(3-dimethylamino-2-ethenylketo)phenyl)-2-oxooxazolidin-5-ylmethyl]acetamideas a white solid. mp 191°-192° C.; ¹ H-NMR (CDCl₃) δ: 7.95 (d,J=7Hz,2H), 7.83 (d,J=13 Hz,1H), 7.58 (d,J=7 Hz,2H), 6.50 (m,1H), 5.75(d,J=13 Hz,1H), 4.83 (bs,1H), 4.12 (t,1H), 3.83 (dd,1H), 3.67 (m,2H),3.17 (bs,3H), 3.00 (bs,3H), 2.05 (s,3H); MS: m/e 331.1537 (M⁺), calcd.for C₁₇ H₂₁ N₃ O₄ : 331.1530.

A solution of the above compound (325 mg, 0.98 mmol) in methanol (3 mL)was treated with hydroxylamine-O-sulfonic acid (125 mg, 1.08 mmol) atroom temperature for 45 minutes. It was poured into saturated sodiumbicarbonate solution. The resulting solid was collected and washed withwater to give, after drying, 167 mg (57%) of the product as a whitesolid. mp 175°-178° C. (dec); ¹ H-NMR (d₆ -DMSO) δ: 8.63 (bs,1H), 8.28(bs,1H), 7.92 (d,J=7 Hz,2H), 7.72 (d,J=7 Hz,2H), 7.00 (bs,1H), 4.77(bs,1H), 4.20 (t,1H), 3.82 (t,1H), 3.43 (m,2H), 1.87 (s,3H); MS: m/e301.1081 (M⁺), calcd. for C₁₅ H₁₅ N₃ O₄ : 301.1061.

EXAMPLE 131 Preparation of(l)-[3-(4-(2-Methyl-4-thiazolyl)phenyl)-2-oxooxazolidin-5-ylmethyl]azide(I, Ar=2-methyl-4-thiazolyl, Q=N₃)

A solution of (l)-5-azidomethyl-N-[3-(4-acetyl-phenyl-2-oxooxazolidin](2.47 g, 9.5 mmol) in chloroform (30 mL) was treated with bromine (0.53mL, 10.45 mmol) at room temperature for 15 minutes. The solvent wasremoved and the residue was taken up with 10% methanol/methylenechloride. The resulting solid was filtered off and the solvent of thefiltrate was removed to afford the crude product which was purified byflash column chromatography to yield 2.15 g (68%) of the bromoacetylcompound. ¹ H-NMR (CDCl₃) δ: 8.00 (d,J=7 Hz,2H), 7.67(d,J=7 Hz,2H), 4.83(m,1H), 4.40 (s,2H), 4.15 (t,1H), 3.93 (dd,1H), 3.70 (2dd,2H).

A mixture of the above bromoacetyl compound (200 mg, 0.59 mmol) andthioacetamide (55 mg, 0.7 mmol) in toluene (3 mL) was refluxed for sixhours. The solvent was removed, the residue was diluted with 10%methanol/methylene chloride, washed with saturated brine and dried (Na₂SO₄). The crude product was purified by flash column chromatography togive 140 mg (76%) of the title compound, ¹ H-NMR (d₆ -acetone) δ: 8.00(d,J=7 Hz,2H), 7.70 (d,J=7 Hz,2H), 7.67(s,1H), 5.00 (m,1H), 4.30 (t,1H),4.00 (dd,1H), 3.83 (m,2H), 2.73 (s,3H).

The title compound was converted into its acetamide compound (I,Ar═2-methyl-4-thiazolyl, B═NHCOCH₃) by the procedure described in U.S.Pat. No. 4,705,799.

By using the procedures described in Examples 130 and 131, the followingcompounds in Table VIII were prepared or can be prepared.

                  TABLE VIII                                                      ______________________________________                                         ##STR88##                                                                    Ex.  Ar             Q         Isomer                                                                              m.p. (°C.)                         ______________________________________                                        130  5-isoxazolyl   NHCOCH.sub.3                                                                            l     175-178                                   131  2-methyl-4-thiazolyl                                                                         N.sub.3   l     NMR                                       132  2-methyl-4-thiazolyl                                                                         NHCOCH.sub.3                                                                            l     179-180                                   133  1H-pyrazol     NHCOCH.sub.3                                                                            l     235-236 (dec)                             134  2-amino-4-thiazolyl                                                                          NHCOCH.sub.3                                                                            l     171-174 (dec)                             135  2-amino-4-pyrimidinyl                                                                        NHCOCH.sub.3                                                                            l     258 (dec)                                 136  5-oxazolyl     NHCOCH.sub.3                                                                            l     200 (dec)                                 ______________________________________                                    

DOSAGE FORMS

The antibacterial agents of this invention can be administered by anymeans that produces contact of the active agent with the agent's site ofaction in the body of a mammal. They can be administered by anyconventional means available for use in conjunction withpharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents. They can be administered alone, butare generally administered with a pharmaceutical carrier selected on thebasis of the chosen route of administration with standard pharmaceuticalpractice.

The dosage administered will, of course, vary depending upon knownfactors such as the pharmacodynamic characteristics of the particularagent, and its mode and route of administration; age, health, and weightof the recipient; nature and extent of symptoms; kind of concurrenttreatment; frequency of treatment; and the effect desired. Usually, adaily dosage of active ingredient can be about 5 to 20 milligrams perkilogram of body weight. Ordinarily, when the more potent compounds ofthis invention are used, 5 to 15, and preferably 5 to 7.5 milligrams perkilogram per day, given in divided doses 2 to 4 times a day or insustained release form, is effective to obtain desired results. Thesedrugs may also be administered parenterally.

Projected therapeutic levels in humans should be attained by the oraladministration of 5-20 mg/kg of body weight given in divided doses twoto four times daily. The dosages may be increased in severe orlife-threatening infections.

Dosage forms (compositions) suitable for internal administration containfrom about 1.0 milligram to about 600 milligrams of active ingredientper unit. In these pharmaceutical compositions, the active ingredientwill ordinarily be present in an amount of about 0.5-95% by weight basedon the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelation capsules contain the active ingredient and powdered carriers,such as lactose, sucrose, manitol, starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration contain preferably a watersoluble salt of the active ingredient, suitable stabilizing agents, and,if necessary, buffer substances. Antiooxidants such as sodium bisulfate,sodium sulfite, or ascorbic acid either alone or combined are suitablestabilizing agents. Also used are citric acid and its salts and sodiumEDTA. In addition, parenteral solutions can contain preservatives, suchas benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, A. Osol, a standard reference text in thisfield.

Useful pharmaceutical dosage forms for administration of the compoundsof this invention can be illustrated as follows:

CAPSULES

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 75 milligrams of powderedactive ingredient, 150 milligrams of lactose, 24 milligrams of talc, and6 milligrams of magnesium stearate.

SOFT GELATIN CAPSULES

A mixture of active ingredient in soybean oil is prepared and injectedby means of a positive displacement pump into gelatin to form softgelatin capsules containing 75 milligrams of the active ingredient. Thecapsules are washed and dried.

TABLETS

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 75 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 250 milligrams for microcrystalline cellulose, 11 milligramsof cornstarch and 98.8 milligrams of lactose. Appropriate coatings maybe applied to increase palatability or delay absorption.

INJECTABLES

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

SUSPENSIONS

An aqueous suspension is prepared for oral administration so that each 5milliliters contain 75 milligrams of finely-divided active ingredient,200 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodiumbenzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 millilitersof vanillin.

UTILITY

Test results indicate that the compounds of this invention arebiologically active against gram positive bacteria including multipleantibiotic resistant strains of staphylococci and streptococci. Thesecompounds are potentially useful for the treatment of both human andanimal bacterial infections including diseases of the respiratory,gastrointestinal, genito-urinary systems; blood; interstitial fluids;and soft tissues.

As shown in Table IX, compounds of Formula (I) exert an in vitroantibacterial effect. A standard microdilution method (NationalCommittee for Clinical Standards. Tentative standard M7-T. Standardmethods for dilution antimicrobial susceptibility tests for bacteriathat grow aerobically. National Committee for Clinical LaboratoryStandards, Villanova, Pa., 1982) with Mueller-Hinton broth is used todetermine the 24-hour minimal inhibitory concentrations (MIC's) for teststrains of Staphylococcus aureus and Escherichia coli.

The in vivo potency of these compounds is exemplified by the datasummarized in Table X. Determinations of in vivo efficacy are performedby inoculating mice intraperitoneally with cultures of the infectingorganism diluted to produce 100% mortality in control animals withintwenty-four hours. The culture of S. aureus used to infect the animalswas diluted to the required bacterial density using 5% aqueous hoggastric mucin. The compounds are dissolved or suspended in 0.25% aqueousMethocel® (Methocel®: Hydroxypropyl Methylcullulose, E15 Premium, DowChemical Company) for oral administration or sterile distilled watercontaining 5% dimethylsulfoxide (Fisher Scientific Company, Fairlawn,N.J.) for subcutaneous administration. The mice are dosed at one hourand at four hours post-infection. Mortality is recorded daily until testdetermination seven days post infection. The number of survivors in eachtreatment group on the seventh day after infection is used in thecalculation of the ED₅₀, the dose of compound that protects 50% of themice (Litchfield, J. T. and Wildoxon. A simulated method for evaluatingdose-effect experiments. J. Pharmacol Exp. Ther., 98:99-113, 1949).

                  TABLE IX                                                        ______________________________________                                        In Vitro Broth Microdilution                                                  Minimal Inhibitory Concentrations (MIC's)                                                Minimum Inhibitory Concentration                                   Example    (μg/mL)                                                         No.        Staphylococcus aureus                                                                        Escherichia coli                                    ______________________________________                                        3          0.5            >128                                                4          0.5            >128                                                7          2              >128                                                8          <0.13          >128                                                9          <0.13          >128                                                10         0.5            >128                                                20         8              >128                                                21         <0.13          >128                                                22         0.25           >128                                                23         1              >128                                                24         8              >128                                                25         2              >128                                                26         1              >128                                                27         0.5            >128                                                28         <0.13          >128                                                29         4              >128                                                30         4              >128                                                37         0.25           >128                                                38         64             >128                                                43         4              >128                                                44         4              >128                                                45         0.5            >128                                                46         4              >128                                                47         0.5            >128                                                48         <0.13          >128                                                49         1              >128                                                50         0.5            >128                                                57         1              >128                                                58         1              >128                                                59         2              >128                                                60         1              >128                                                61         2              >128                                                62         2              >128                                                63         0.25           >128                                                64         4              >128                                                65         2              >128                                                66         0.5            >128                                                67         0.25           >128                                                68         0.25           >128                                                69         0.25           >128                                                70         2              >128                                                71         2              >128                                                73         0.5            >128                                                74         8              >128                                                75         <0.13          >128                                                85         <0.13          >128                                                86         2              >128                                                87         32             >128                                                88         <0.13          >128                                                89         2              >128                                                92         2              >128                                                113        16             >128                                                114        0.5            >128                                                115        16             >128                                                116        16             >128                                                117        4              >128                                                118        4              >128                                                119        <0.13          >128                                                130        1              >128                                                132        4              >128                                                133        4              >128                                                134        8              >128                                                135        4              >128                                                136        1              >128                                                ______________________________________                                    

                  TABLE X                                                         ______________________________________                                        In Vivo Activity of Compounds Against                                         Staphylococcus Aureus in an Acute Lethal Mouse Model                                    ED.sub.50 (mg/kg)                                                   Example     Oral        Subcutaneous                                          No.         Administration                                                                            Administration                                        ______________________________________                                        3           2.9         2                                                     4           22          39.7                                                  7           NT          >90                                                   8           >90         >90                                                   9           >90         16.8                                                  10          NT          NT                                                    20          >90         >90                                                   21          44.7        >90                                                   22          >90         >90                                                   23          17.3        24.3                                                  24          >90         >90                                                   25          13.9        5.8                                                   26          NT          NT                                                    27          6.6         7.6                                                   28          52.6        30                                                    29          16.1        9.8                                                   30          16.1        9.8                                                   37          <1.2        0.6                                                   38          NT          >90                                                   43          6.4         3.7                                                   44          8.6         3.7                                                   45          NT          13.9                                                  46          NT          30                                                    47          NT          NT                                                    48          NT          NT                                                    49          65.2        >90                                                   50          NT          6.5                                                   57          18          10                                                    58          13.8        2                                                     59          7           2.7                                                   60          30          5.5                                                   61          47.4        2.7                                                   62          51.9        10                                                    63          >90         >90                                                   64          50          11                                                    65          NT          4.3                                                   66          NT          NT                                                    67          4.5         30                                                    68          2.2         0.7                                                   69          4           1.2                                                   70          17          10                                                    71          51.9        >90                                                   73          11.8        5                                                     74          NT          17.1                                                  75          NT          NT                                                    85          1.3         0.5                                                   86          NT          15.5                                                  87          16.1        9.8                                                   88          1.6         0.5                                                   89          2           <3.3                                                  92          NT          NT                                                    113         >90         68.3                                                  114         8.1         >100                                                  115         NT          NT                                                    116         NT          6.4                                                   117         NT          NT                                                    118         NT          NT                                                    119         6.2         5                                                     130         6           6                                                     132         NT          17                                                    133         22          22                                                    134         56.5        47                                                    135         68          NT                                                    136         14.8        51.9                                                  ______________________________________                                         NT = Not Tested                                                          

What is claimed is:
 1. An aryl benzene oxazolidinone of the formula##STR89## wherein, for the 1, and mixtures of the d and 1 stereoisomersof the compoundAr is an aromatic group selected from the groupconsisting of a diazinyl group optionally substituted with X and Y; Xindependently is H, --NO₂, --S(O)_(n) R₁, --S(O)₂ --N═S(O)_(p) R₂ R₃,##STR90## alkyl of 1 to 8 carbons optionally substituted with halogen,OH, ═O other than at the carbon atom contiguous with Ar, S(O)_(n) R₂₄,or NR₅ R₆, alkenyl or 2-5 carbons or cycloalkyl of 3-8 carbons; R₁ is C₁-C₄ alkyl, optionally substituted with halogen, OH, CN, NR₅ R₆ or CO₂ R₈; C₂ -C₄ alkenyl; --NR₉ R₁₀ ; --N₃ ; ##STR91## --NG₂ ; --NR₉ G--⁻ NGM⁺ ;R₂ and R₃ are independently C₁ -C₂ alkyl or, taken together are--(CH₂)_(q) --; R₄ is alkyl of 1-4 carbons, optionally substituted withhalogen; R₅ and R₆ are independently H, alkyl of 1-8 carbons, cycloalkylof 8 carbons, --(CH₂)_(t) OR₈, --(CH₂)_(t) R₁₁ R_(11a), or --O(CH₂)_(t)NR₁₁ R_(11a) ; or taken together are --(CH₂)₂ O(CH₂)₂ --, --(CH₂)_(t)CH(COR₄)--, or ##STR92## R₇ is --NR₅ R₆, --OR₅ or ##STR93## R₈ is H oralkyl of 1-4 carbons; R₉ is H, C₁ -C₄ alkyl or C₃ -C₈ cycloalkyl; R₁₀ isH, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₃ -C₄ cycloalkyl, --OR₈ or NR₁₁R_(11A) ; R₁₁ and R_(11A) are independently H or C₁ -C₄ alkyl, or takentogether, are --(CH₂)_(r) --; G is Cl, Br or I; Y independently is H, F,Cl, Br, OR₈, alkyl of 1-3 carbons, or NO₂ ; M is a physiologicallyacceptable cation; n is 0, 1 or 2; p is 0 or 1; q is 3, 4 or 5; r is 4or 5; t is 1, 2 or 3; Q is --NH₂, ##STR94## or N₃ ; R₁₂ is H, C₁ -C₁₀alkyl or C₃ -C₈ cycloalkyl; R₁₃ is H; C₁ -C₄ alkyl optionallysubstituted with halogen, C₂ -C₄ alkenyl; C₃ -C₄ cycloalkyl; phenyl;--CH₂ OR₁₅ ; --CH(OR₁₆)OR₁₇ ; --CH₂ S(O)_(v) R₁₄ ; ##STR95## --OR₁₈ ;--SR₁₄ ; --CH₂ N₃ ; an aminoalkyl group derived from an a-amino acidselected from the group consisting of glycine, L-alanine, L-cysteine,L-proline, and D-alanine; --NR₁₉ R₂₀ ; or --C(CH₂)R₂₁ R₂₂ ; R₁₄ is C₁-C₄ alkyl, optionally substituted with halogen; R₁₅ is H or C₁ -C₄alkyl, optionally substituted with halogen; R₁₆ and R₁₇ areindependently C₁ -C₄ alkyl or, taken together are --(CH₂)_(m) --; R₁₈ isC₁ -C₄ alkyl or C₇ -C₁₁ aralkyl; R₁₉ and R₂₀ are independently H or C₁14 C₂ alkyl; R₂₁ and R₂₂ are independently H, C₁ -C₄ alkyl, C₃ -C₆cycloalkyl, phenyl; u is 1 or 2; v is 0, 1 or 2; m is 2 or 3; s is 2, 3,4 or 5; R₂₃ is H, alkyl of 1-8 carbons optionally substituted withhalogen, cycloalkyl of 3-8 carbons, alkyl of 1-4 carbons substitutedwith one of --S(O)_(n) R₂₄, --OR₈, ##STR96## or --NR₅ R₆ ; or alkenyl of2-5 carbons optionally substituted with CHO or CO₂ R₈ ; R₂₄ is alkyl of1-4 carbons or cycloalkyl of 3-8 carbons; and R₂₅ is R₆ or NR₅ R₆ ;or apharmaceutically suitable salt thereof.
 2. An oxazolidinone of claim 1wherein Q is --NHC(═O)R₁₃ where R₁₃ is H, CH₃, --OR₁₈, CH₂ Cl, CH₂ OH,or CH₂ OCH₃.
 3. An oxazolidinone of claim 2 wherein Q is --NHC(═O)R₁₃.4. A pharmaceutical composition consisting essentially of a suitablepharmaceutical carrier and an effective amount of a compound of claim 1.5. A pharmaceutical composition consisting essentially of a suitablepharmaceutical carrier and an effective amount of a compound of claim 2.6. A pharmaceutical composition consisting essentially of a suitablepharmaceutical carrier and an effective amount of a compound of claim 3.7. A method of treating a bacterial infection in a mammal comprising:administering to the mammal an antibacterial amount of a compound ofclaim 1.